Lyophilisate of treosulfan

Abstract

A lyophilisate of treosulfan is described which possesses favourable characteristics in terms of a short reconstitution time and a high purity and stability and which is particularly useful in the treatment of cancer and for conditioning therapy before transplantation of bone marrow or blood stem cells.

The invention claimed is: 
     
       1. A lyophilisate of treosulfan, wherein the lyophilisate comprises crystalline form B of treosulfan exhibiting an X-ray powder diffraction pattern having characteristic peaks at 20.87 and 23.47±0.20 degrees 2Θ. 
     
     
       2. The lyophilisate according to  claim 1 , wherein the crystalline form B exhibits an X-ray powder diffraction pattern having characteristic peaks at 20.87, 23.47, 26.20, 29.65, 30.81, 34.54, 35.30, 36.87 and 46.24±0.2 degrees 2Θ. 
     
     
       3. The lyophilisate according to  claim 1 , wherein the crystalline form B exhibits an X-ray powder diffraction pattern essentially as shown in  FIG.  1   . 
     
     
       4. The lyophilisate according to  claim 1 , wherein the crystalline form B exhibits an X-ray powder diffraction pattern having no peaks in at least one of the following regions a to f, expressed as degrees 2Θ: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Region 
                   Degrees 2Θ 
                 
                     
                     
                 
                     
                   a 
                   19.00-19.50 
                 
                     
                   b 
                   20.00-20.65 
                 
                     
                   c 
                   21.50-23.21 
                 
                     
                   d 
                   23.75-24.95 
                 
                     
                   e 
                   27.40-28.35 
                 
                     
                   f 
                   30.00-30.60 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       5. The lyophilisate according to  claim 1 , which comprises at least 96% by weight of the crystalline form B, relative to the combined amount of crystalline form B and crystalline form A. 
     
     
       6. The lyophilisate according to  claim 1 , which comprises at least 75% by weight of the crystalline form B, relative to the amount of lyophilisate. 
     
     
       7. The lyophilisate according to  claim 1  which comprises less than 20% by weight of amorphous phase, relative to the amount of lyophilisate. 
     
     
       8. The lyophilisate according to  claim 1 , which comprises at least 95% by weight of treosulfan. 
     
     
       9. The lyophilisate according to  claim 1 , which comprises less than 0.2% by weight of methanesulfonic acid. 
     
     
       10. The lyophilisate according to  claim 1 , which comprises less than 1% by of water. 
     
     
       11. The process for preparing the lyophilisate according to  claim 1 , which process comprises freeze-drying an aqueous solution comprising treosulfan. 
     
     
       12. The process according to  claim 11 , wherein the aqueous solution comprises water and optionally one or more organic solvents. 
     
     
       13. The process according to  claim 12 , wherein the organic solvent is acetic acid. 
     
     
       14. The process according to  claim 11 , which comprises
 (a) providing the aqueous solution having a first temperature, 
 (b) freezing the aqueous solution, wherein the aqueous solution is cooled from the first temperature to a freezing temperature at a cooling rate of not more than 3 K/min, and 
 (c) drying the frozen solution obtained in step (b) to give the lyophilisate. 
 
     
     
       15. The process according to  claim 14 , wherein the cooling rate in step (b) is not more than 2 K/min. 
     
     
       16. The process according to  claim 11 , wherein the first temperature is from 15° C. to 95° C. 
     
     
       17. The process according to  claim 11 , wherein the freezing temperature is −40° C. or less. 
     
     
       18. The process according to  claim 11 , wherein the frozen solution is kept at the freezing temperature for at least 1 hour. 
     
     
       19. The process according to  claim 14 , wherein the drying in step (c) includes a primary drying which is carried out by subjecting the frozen solution to a temperature of −25° C. or higher and subjecting the frozen solution to a pressure of 0.03 to 1.0 mbar,
 or 
 the drying in step (c) includes a primary drying which is carried out by subjecting the frozen solution to a temperature of 0° C. or higher and subjecting the frozen solution to a pressure of 0.03 to 1.0 mbar. 
 
     
     
       20. The process according to  claim 19 , wherein the primary drying is carried out for at least 5 hours. 
     
     
       21. The process according to  claim 19 , wherein after the primary drying a secondary drying is carried out by subjecting the product of the primary drying to a temperature of at least 30° C. and subjecting the product of the primary drying to a pressure of 0.03 to 1.0 mbar. 
     
     
       22. A method of treating cancer comprising preparing a pharmaceutical composition from the lyophilisate according to  claim 1  and administering the pharmaceutical composition to a patient suffering from cancer. 
     
     
       23. A method comprising preparing a pharmaceutical composition from the lyophilisate according to  claim 1  and administering the pharmaceutical composition to a patient in need thereof as a conditioning therapy before transplantation of bone marrow or of blood stem cells into the patient.